Project Summary Spinal muscular atrophy (SMA) is an inherited neurodegenerative disease characterized by motor neuron loss and skeletal muscle atrophy. SMA is caused by ubiquitous deficiency in the survival motor neuron (SMN) protein and, given the well-established direct correlation between the degree of SMN reduction and disease severity, most SMA therapeutic approaches to date have focused on increasing the levels of SMN expression through multiple strategies. The remarkable success of several of these approaches in preclinical studies has led to ongoing clinical trials. However, no effective therapy is currently available for SMA, which remains the most common genetic cause of death in infancy. Therefore, there is an urgent need to identify treatments that can either restore SMN levels or correct the deficits downstream of SMN depletion in SMA patients. Furthermore, while greater knowledge of the central role of SMN in RNA processing combined with characterization of animal models of SMA have significantly advanced our understanding of the disease, the precise molecular and cellular events that underlie the dysfunction and death of SMA motor neurons remain elusive. Clearly, identification of cellular factors and pathways contributing to synaptic dysfunction and selective neuronal death induced by SMN deficiency is not only essential to understand disease mechanisms but may also broaden the range of targets for developing SMA therapies that can complement SMN upregulation approaches. This project aims to characterize a novel cellular pathway that is dysregulated in SMA in order to increase our understanding of the downstream events induced by SMN deficiency that are relevant to the disease process, which may also represent novel potential therapeutic targets. In a chemical genetic screen for agents that suppress cellular phenotypes induced by SMN deficiency in cultured mammalian cells, we identified p38MAPK inhibitors as candidate modifiers of SMN biology. Further studies revealed that SMN deficiency induces p38MAPK activation in vivo and its pharmacological inhibition improves motor deficits in SMA mice. Building on these findings, here we propose to determine the precise contribution of p38MAPK dysregulation to motor dysfunction using both pharmacological and genetic approaches in a mouse model of SMA. In Aim 1, we will perform a longitudinal analysis of the effects of inhibiting the p38MAPK pathway on morphological and functional abnormalities induced by SMN deficiency in the SMA motor system. In Aim 2, we will carry out a comprehensive set of studies to determine the p38MAPK-dependent molecular and cellular events that may contribute to SMA pathology, with a particular emphasis on the mechanisms of motor neuron degeneration. Collectively, these studies are designed to establish activation of the p38MAPK pathway as a key component of the pathogenic cascade induced by SMN deficiency during the disease process and to provide proof-of-concept for its inhibition as a novel, SMN-independent therapeutic approach for SMA.